The objective of this interdisciplinary study is to elucidate the specific role of the ascending serotonergic (5-HT) and noradrenergic (NE) projections upon the functional properties of neurons in primate neocortex and to test the hypothesis that these neurotransmitters regulate the discharge patterns of cortical neurons that are active in specific behavioral and cognitive tasks. Extracellular recording techniques will be employed to monitor patterns of neuronal discharge and of directionality of single neurons in motor, premotor and pariental cortex in awake, behaving monkeys. Patterns of neuronal activity will be compared in normal cortex, in zones locally depleted of 5-HT or NE and after iontophoretic replacement of these neurotransmitters. For these studies, localized zones of cortex will be selectively ablated of 5-HT or NE axons by micro-injections of specific neurotoxins. These denervated zones will be extensively characterized for selective depletion and non-specific damage by a battery of histologic, immunohistochemical, and biochemical measures. To determine whether monoaminergic neurons have localized or widespread effects upon neocortex, the topographic pattern of raphe-cortical projections will be analyzed by retrograde transport of fluorescent dyes, and the intracortical trajectory of monoamine axons will be determined by analysis of sections through the denervated cortical zones. This study should contribute new information, particularly relevant for man, concerning the functional organization of the monoamine neurons and should lead us to identify those parameters of cortical neuronal discharge that are influenced by these brainstem projections. These neurons, which are affected by widely used psychotropic drugs, are involved in cognitive functions and may regulate vigilance, mood, sleep, and attention; abnormalities of these neuron systems have been implicated in neurologic and pshychiatric disorders, especially in manic-depressive psychoses and in the dementias.